Gastric cancer is mostly associated with poor survival and ranks 5 in Europe in terms of incidence. Because it is often detected at late stages, available treatments are mostly inefficient.
Microtubule targeting agents of the taxane class, like docetaxel, have been used for almost a decade to treat refractory breast cancer, and they have also been foreseen to treat gastric cancer. However, only few patients could benefit from docetaxel treatment, mostly because of severe side effects (Baker, Ajani et al. 2009). Nevertheless, above 80 clinical trials recorded at the NIH still evaluate—or will aim at doing so when recruitment will be completed—docetaxel as an anticancer agent in combination with other chemotherapeutic agents, including 5-fluorouracile, cisplatin, capecitabin, epirubicin, Gleevec®, bevacizumab, among several others. Hence, docetaxel is still believed to be promising for the treatment of gastric cancer.
Statins are used as anti-hypercholesterolemia drugs, but they also bear potential as either cancer preventive or adjuvant therapies (Demierre, Higgins et al. 2005). There has been some dispute in the literature concerning the chemoprevention statins may exert on cancer occurrence (Bjerre and LeLorier 2001; Katz 2005). By contrast, analyses in experimental models have mostly converged towards the concept that statins may increase the efficacy of cancer cell killing triggered by several classes of drugs and used to target various types of cancer cells (Graaf, Richel et al. 2004; van der Spek, Bloem et al. 2009; Sane, Mynderse et al. 2010; Zheng, Cui et al. 2010). Hence, combinations of various statins with DNA damaging agents like topoisomerase inhibitors, cisplatin or 5-fluorouracile have shown increased cell death, reduced tumour growth or reduction in metastases (Agarwal, Bhendwal et al. 1999; Kozar, Kaminski et al. 2004; Martirosyan, Clendening et al. 2010; Taylor-Harding, Orsulic et al. 2010).
The molecular mechanisms triggered in response to statins or docetaxel have been deeply investigated in cell culture and in animal models. Both drugs are capable of triggering apoptosis (Schimming, Mason et al. 1999; Sassano and Platanias 2008). Their sub-cellular targets may be either shared or quite distinct. Docetaxel promotes microtubule assembly and stabilize the polymers against depolymerization, thereby inhibiting microtubule dynamics. As a result, mitotic progression is restricted, which leads to inhibition of cell proliferation. Statins have no reported effects of the activity of the mitotic spindle. Docetaxel triggers the degradation of the anti-apoptotic Bcl-2 protein through increased phosphorylation, and statins suppress the Bcl-2 protein (Wong, Dimitroulakos et al. 2002). Both docetaxel and statins inhibit angiogenesis, although this may depend on the administered dose for statins. Statins can induce the cell cycle inhibitor protein p21, whereas docetaxel has no effect on p21 expression (Gray-Bablin, Rao et al. 1997; Demidenko, Halicka et al. 2005). One study had shown that the combination of paclitaxel and lovastatin had a synergistic effect on apoptosis of leukemia cells (Holstein and Hohl 2001).
However, leukaemia is clearly a quite different cancer type than solid tumors. In particular, the local microenvironment of cancer cells is completely different in a non solid tumor such as leukaemia, in which cancer cells freely circulate and do not form a sort of solid organ, and in solid tumors, in which the tumor forms a complex and organized entity, resulting in complex interactions between various cancer cells types and reduced accessibility of at least some cancer cells to drugs due to their localization in the tumor solid mass;
To conclude, taxanes and statins have been tested as anticancer therapy but none of the above categories of agents have proven liable to completely treat individuals afflicted with cancer, and specially solid tumors such as gastric cancers, which are notably associated with poor prognosis. Thus, there is a need for new therapeutic alternatives that could provide new perspectives in particular in gastric cancer treatment.